Abstract Despite significant reduction in acute rejection rates, long-term allograft survival remains stagnant, hovering at around a half-life of 10 years for most transplanted organs. A principal cause of poor long-term graft outcomes is persistent host immune activation leading to chronic rejection. We propose here that persistent immune activation is driven by the innate immune system, specifically by monocytes which recognize allogeneic non-self and acquire memory to it. Monocytes sense non-MHC and MHC polymorphisms on allogeneic tissues and acquire the ability to mount an enhanced recall response specific to donor MHC. This response results in sustained graft infiltration by mature, IL-12+, monocyte-derived DCs that maintain an inflammatory Th1 response and are critical for allograft rejection. The goal of this grant application is to investigate in Aim 1 the molecular and cellular mechanisms of monocyte memory generation and specificity to allogeneic MHC, and to determine in Aim 2 the contribution of monocyte memory to chronic allograft rejection. Completion of the proposed studies is likely to have a significant impact on organ transplantation by uncovering novel innate immune system targets to prevent or treat rejection.